Attachment A - Guidelines for Submission of Proposed Studies to the Research Involving Human Subjects Committee (RIHSC) for ReviewAttachment B - Transmittal Memorandum to Accompany Projects for Research Involving Human Subjects Review (RIHSC)

1. PURPOSE

The purpose of this Guide is to describe membership,responsibilities,functions, and procedures of the Food and Drug Administration's Research Involving Human Subjects Committee (RIHSC).

2. APPLICABILITY

This Guide applies to research, development, and related activities (e.g., biomedical, behavioral, survey, etc.) which will involve human subjects in any capacity and which are:

1. conducted in FDA facilities;

2. conducted under contract to, or grant by, the Food and Drug Administration;

3. in non-FDA facilities in which FDA scientists collaborate or are otherwise significantly involved;

4. conducted under an Interagency Agreement between FDA and another agency or agencies; or

5. imposed by regulation in the form of a protocol or test with specific requirements (such as dose, subject population, duration, number of exposures to risks, etc.) upon sponsors, involved in or conducting research or studies relating to the marketing of products subject to FDA regulation.

3. AUTHORITY

The Research Involving Human Subjects Committee (RIHSC) was established on October 3, 1969 to implement PHS policy on the protection of human subjects. A major aspect of this policy was to establish an Agency review committee to consider the ethical and human protection aspect of both intramural and extramural research. This policy was subsequently codified into regulation (45 CFR 46, 21 CFR 50 and 21 CFR 56). The RIHSC operates under the Commissioner's authority and in conformance with HHS and FDA regulations and policy.

4. RESPONSIBILITIES

The RIHSC reviews all intramural and extramural Memoranda of Need (MON) (initial or renewal) or protocol, (contractor, grantee, or intramural) which will involve human subjects. The review is directed primarily to the ethical and human protection aspects of the proposal or protocol. Contracts, grants, or Interagency Agreements (IAGs) may not be negotiated or awarded unless the RIHSC has reviewed and approved the proposal. The RIHSC may grant an "Approval in Principle" in order to allow a contract to be negotiated or a grant to be awarded.

The RIHSC must be advised of any changes in an approved protocol, including repetition of the study, and it, approval must be obtained before significant changes can be made in the protocol (examples of significant changes are those which may affect the potential risks to participants, changes in investigators, changes in facilities, etc.) with the exception that changes which are necessary to reduce risks to participants may be made prior to RIHSC notification and approval.

The RIHSC reviews all protocols or tests which will involve human subjects and which will be imposed by the Agency by regulation upon sponsors, investigators, or other individuals or organizations involved in or conducting research or studies related to the marketing or development of products regulated by the Food and Drug Administration. The review is directed primarily to the ethical and human protection aspects of the protocol or test. Such protocols or tests may not be issued until they have been approved by the RIHSC. This review does not include research protocols which are routinely submitted to the FDA by researchers or by sponsors as part of an IND or IDE. If asked, the RIHSC will offer comments on the human protection aspects of the proposal or consent form.

The RIHSC functions as the FDA Institutional Review Board for FDA intramural research studies involving human subjects. In this capacity, the RIHSC performs both the initial as well as continuing reviews. Scheduling for continuing reviews will depend upon the nature of the study (expected duration, risks, complexity, etc.) but the review will occur at least annually. The RIHSC operates under the requirements set forth by the HHS and FDA regulations for IRBs (45 CFR 46 and 21 CFR 56).

5. MEMBERSHIP

The RIHSC shall be composed of persons with varying backgrounds to promote a complete and adequate review of activities submitted for its review. (21 CFR 56.107).

The Chairperson of the RIHSC shall be appointed by the Commissioner of Food and Drugs. The chairperson may designate an alternate who serves in his (or her) absence.

Representatives of the following organizational units will be designated by the respective heads of the units:

Office of Management and Operations

Office of Regulatory Affairs

Office of Health Affairs

Office of Biologics

Office of Drugs

Bureau of Foods

Bureau of Medical Devices

Bureau of Radiological Health

Bureau of Veterinary Medicine

Equal Employment Opportunity Office

Office of the General Counsel

The representative from the Office of Health Affairs will serve as the Executive Secretary of the RIHSC. Heads of units will designate representatives and alternates for terms of 3 years.

In addition to the FDA-organizational units, the RIHSC will have at least one public member who is not otherwise affiliated with the institution and who is not part of the immediate family of a person who is affiliated with the institution. The public member or members should have backgrounds in areas other than bio-medical in order to reflect local attitudes and views. Public members will be recruited by the Office of Health Affairs.

6. MEETINGS

The RIHSC will meet periodically to review proposals or protocols. Emergency meetings will be called by the Chairperson of the RIHSC or by a designee. All members will be notified of meeting. RIHSC meetings will normally be closed to the public. The Chairperson will rule on requests to attend meetings of the RIHSC. Minutes of meetings will be prepared and distributed to members.

A quorum of the RIHSC will be not only a simple majority of the members but must include at least one public member and one physician. (21 CFR 56.107)

The RIHSC may invite FDA staff involved with the research proposal or protocol to attend the meetings at which the proposal is reviewed and to serve as a resource person(s). Other interested persons may be invited to attend the meeting(s) if their presence may aid in the review of proposals.

Only RIHSC members or their alternates may vote on proposals. RIHSC members representing FDA bureaus or offices must abstain from voting on proposal submitted by their bureau or office.

7. REVIEW

Researchers or project officers (in the case of extramural studies) should submit the following information to aid the RIHSC review:

Note: The bureau's or unit's scientific/technical committee may review some of the material identified in Attachment B and this may be addressed in its memorandum and/or minutes of meeting (e.g., facilities, qualifications of investigator, etc.). The bureau's or unit's science review committee is responsible for decisions regarding the need for the study and for determining that it is appropriate that FDA conduct or support the study. MONs for funding of external studies are reviewed by the Office of Health Affairs (Science).

2. A memorandum from the bureau's or unit's, science/technical review committee indication that the proposal or protocol has been reviewed and that it has scientific merit, that the potential risks are offset by potential benefits to either the participants or to society, and that there is no suitable alternative to the human protection aspects of the proposal or protocol, will retain the science/technical review committee's memorandum as a part of the file).

No RIHSC member may participate in the review of a project, proposal, or protocol if he or she is involved in its scientific or technical direction, except to provide information requested by the RIHSC.

All proposals and protocols will be circulated to the members of the RIHSC member. Submissions will be assigned to members in rotation. The initial review of protocols will be conducted at meetings. Following discussion by the RIHSC, the Chairperson will determine whether action on the proposal or protocol should be taken at that time. The actions on a proposal or protocol which can be taken by the RIHSC are described in paragraph 10 below. The project officer will be informed of the RIHSC decision by receipt of a memorandum.

8. EXPEDITED REVIEW: PROCEDURE AND CRITERIA

The expedited review procedure was established by the RIHSC to provide adequate and expeditious action on research and extramural studies involving no more than minimal risk. "Minimal risk" means that the risks of harm anticipated in the proposed research are not greater, considering probability and magnitude, than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or test. The expedited review procedure applies both to RIHSC review of extramural studies and RIHSC/IRB review, and reflects the requirements of the regulations [21 CFR 56.110].

1. Procedures for Expedited Review. The expedited review procedure established by the RIHSC involves the following steps:

a. The proposed study is processed by the Executive Secretary to determine whether the criteria for expedited review has been met. If so, the study is sent to a primary reviewer (a non-Office of Health Affairs member of RIHSC) for an initial review. The initial review is done by the RIHSC member or members designated by Committee or Chairperson.

b. The primary reviewer reviews the relevant documents, such as the MON, protocol and informed consent, and transmits to the Chairperson a recommendation as to what action should be taken (e.g., approval, supplementation, or review by the entire committee).

c. The RIHSC Chairperson reviews the proposal and the recommendations of the primary reviewer and decides whether to endorse the proposal, request a second review, or request review by the entire RIHSC.

d. If a proposal is approved through the expedited review procedure, an approval memorandum is sent to the project officer. The approval memorandum will include the name of the primary reviewer, a summary statement dealing with relevant comments, and the signature of the Chairperson, RIHSC. If the proposal is to be sent to the whole RIHSC for review, the project officer is notified by telephone and memorandum of the date of the meeting.

e. The full RIHSC is informed of studies approved through the expedited review procedure at the next regularly scheduled RIHSC meeting.

2. Categories of Intramural Studies Eligible for Expedited Review.

a. Collection of hair and nail clippings in a non-disfiguring manner; of deciduous teeth; and of permanent teeth if patient care indicates a need for extraction.

b. Collection of excreta and external secretions including sweat and uncannulated saliva; of placenta at delivery; and of amniotic fluid at the time of rupture of the membrane before or during labor.

c. Recording of data from subjects who are 18 years of age or older using noninvasive procedures routinely employed in clinical practice. [This category includes the use of physical sensors that are applied either to the surface of the body or at a distance and do not involve input of matter or significant amounts of energy into the subject or an invasion of the subject's privacy. It also includes such procedures as weighing, electrocardiography, electroencephalography, thermography, detection of naturally occurring radioactivity, diagnostic echography, and electroretinography. This category does not include exposure to electromagnetic radiation outside the visible range (for example, x-rays or microwaves)].

d. Collection of blood samples by venipuncture, in amounts not exceeding 450 milliliters in an eight-week period and no more often than two times per week, from subjects who are 18 years of age or older and who are in good health and not pregnant.

e. Collection of both supra- and subgingival dental plaque and calculus, provided the procedure is not more invasive than routine prophylactic scaling of the teeth, and the process is accomplished in accordance with accepted prophylactic techniques.

f. Voice recordings made for research purposes such as investigations of speech defects.

i. Research on drugs or devices for which an investigational new drug exemption or an investigational device exemption is not required except for certain bioavailability studies which by regulation do not require an IND.

j. Minor changes in previously approved research during the period for which approval is authorized.

3. Criteria for Expedited Review of Extramural Studies. In addition to the categories listed above, the RIHSC may review the following extramural studies under the expedited review procedure:

a. Renewal of a contract, grant, IAG or protocol provided that:

(1) No changes have been made in the procedures originally approved by the RIHSC that would affect the potential risks to the subjects;

(2) No adverse or unexpected reactions have been reported by the investigator;

(3) A current progress report is on file for review by the RIHSC;

b. Memorandum of Need submitted for Approval in Principle;

c Changes in approved study protocols and/or consent forms made by local IRBs.

9. EMERGENCY REVIEW

When a situation calls for emergency use of an investigational product for which RIHSC (IRB) review is required (21 CFR 56.104(c)), the Chairperson or an appropriate alternate will review the circumstances and give approval prior to administration of the investigational product. If the situation does not permit RIHSC review, the emergency use must be reported to the RIHSC within 5 working days. The full RIHSC should be notified of this emergency use at the next regularly scheduled meeting so that members may be assured that emergency procedures are not being used to circumvent human subject protection policies of the institution. The RIHSC will be provided with follow-up information on the emergency procedure for review as required by the RIHSC monitoring regulations.

10. ACTIONS ON PROPOSALS OR PROTOCOLS

The RIHSC may:

1. Approve the proposal or protocol and the necessary consent form(s) as submitted or on the condition that changes requested by the RIHSC are made.

2. Grant the proposal or protocol an "Approval in Principle." This action will allow planning, including contract negotiation or grant processing, to proceed. Approval in Principle" does not permit initiation of any work which will involve human subjects. Specific studies or protocols must be submitted for review and RIHSC approval must be obtained before work can start. Individual protocols under a contract or grant must be submitted for review and approval. (Note: Because of procurement procedures, it is not feasible to extend an "Approval in Principle" to IAGs.)

3. Defer a decision until the submission of further information. This may include referring the proposal to the appropriate bureau or unit scientific review committee for further consideration of specific points. d. Disapprove the proposal or protocol.

4. Refer the proposal or protocol for review by the Ethical Advisory Board. Proposals or protocols in those areas identified by the Ethical Advisory Board, with the approval of the Secretary of DHHS, will be submitted to the Board for a review of their ethical acceptability (45 CFR 46.204). Referral will be made by the Chairperson of the RIHSC through the Commissioner of Food and Drugs.

The Committee's decision will be by majority of the members present and the vote will be recorded in the minutes, as members for, against, and abstaining. The Chairperson will vote only in cases of a tie.

11. CONTINUING REVIEW (INTRAMURAL RESEARCH INVOLVING HUMAN SUBJECTS)

The RIHSC will be responsible for the continuing review of intramural research projects which involve human subjects. The RIHSC will schedule the continuing review at the time of approval based upon the nature of the study (expected duration, potential risks, complexity, etc.). This review will be conducted on at least an annual basis.

Project officers or FDA investigators may be invited to meet with the RIHSC or with designated members to provide reports or updates at the designated intervals. Members of the RIHSC may make site visits and may observe consent procedures as they are being used by the investigators.

12. OFF-SITE NON-FDA FACILITIES RESEARCH ACTIVITIES IN WHICH FDA INVESTIGATORS OR STAFF ARE SIGNFICANTLY INVOLVED

Reviews of research involving human subjects in non-FDA facilities and in which FDA investigators or staff are significantly involved (investigator, co-investigator, protocol concept, and preparation, etc.) will be conducted in the same manner or subjected to comparable review to be comparable and may, after its initial review and approval, defer to an on-site Institutional Review Broad under the following conditions:

1. The institution where the study will be conducted holds an assurance as required by 45 CFR 46.103.

2. The facilities are part of a Federal Government agency which follows review procedures that conform with DHHS regulations, and the institution's review board approves the project and agrees to assume the continuing review responsibilities.

3. The investigator or project officer agrees to advise promptly the FDA RIHSC of any adverse reactions or serious emergent problems, and to report to the FDA RIHSC at designated intervals, which will be at least annually, on the progress of the activity.

13. MISCELLANEOUS

RIHSC approvals, favorable actions, and/or recommendations are subject to review and further restriction by the Commissioner of Food and Drugs, the Assistant Secretary for Health, and by the Secretary of DHHS.

RIHSC disapprovals, restrictions, or conditions cannot be rescinded except by RIHSC action based on new information.

All documents presented or required for initial and continuing review will be kept in the custody of the Office of Health Affairs/Medicine when not in active use and retained there for a period of three years after the date of completion of the project.

ATTACHMENT A

Guidelines for Submission of Proposed Studies to the Research Involving Human Subjects Committee (RIHSC) for Review

1. The function of the RIHSC is to review all studies involving human subjects sponsored by, conducted by, or imposed by specific regulation by the Food and Drug Administration. The RIHSC is primarily concerned with the ethical and human protection issues of proposed studies and serves as the competent Agency authority to assure that appropriate procedures will be employed to protect the rights and welfare of subjects.

2. All submissions should be concise.

3. The following must be submitted for review:

a. Memoranda of Need or grant applications (for which financial support is contemplated) for both domestic and foreign (i.e., Special Foreign Currency Program) projects or Interagency Agreements (IAGs) which will involve human subjects.

b. Individual protocols which involve human subjects and are developed by investigators under contract, grant, Interagency Agreements or by FDA staff members responsible for intramural research. These include medical, behavioral, or psychological studies.

c. Agency-developed protocols or tests which are distributed to or imposed by regulation upon investigators, sponsors, or industry by the Food and Drug Administration and which require volunteer participation (i.e., bioavailability study protocols for marketed drugs).

4. The following information in support of 3(a) must be submitted to the RIHSC:

a. Transmittal memorandum (Attachment B).

b. If known, the qualifications of the responsible investigator, and a description of the facilities to be used by the investigator.

5. The following information in support of 3(b) must be submitted to the RIHSC:

a. Transmittal memorandum (Attachment B).

b. The qualifications of the responsible investigator(s) involved in the study, and a concise description of the facilities and other resources for the accomplishment of the study and the protection of the subjects. If pertinent to the study, a description of the treatment available for emergencies, etc., should be included.

c. A memorandum or letter from the bureau's or unit's scientific review committee indicating that it has reviewed and approved the study.

d. In the case of an IAG under which the research will be conducted at other than FDA facilities, a memorandum indicating that the other agency's human protection committee has reviewed and approved the study and assumes responsibility for continuing review.

6. The following information in support of 3(c) must be submitted to the RIHSC:

a. Transmittal memorandum (Attachment B).

b. A memorandum or letter from the bureau's or unit's scientific review committee indicating that it has reviewed and approved the study.

7. Sixteen copies of the information in support of 3(a) 3(b) and 3(c) should be submitted to the Executive Secretary of the RIHSC (HFY-2).

8. Materials in support of studies which the project officer and the bureau consider eligible for expedited review should include:

a. The study proposal;

b. A statement establishing the scientific merit of the proposal;

c. A statement giving the minimal risk or other criteria, specified in paragraph 8 of this Guide, which make the study eligible for expedited review.

Submission of a transmittal memorandum is not required. If the full RIHSC will need to review he study, materials listed in paragraphs 4, 5 or 6 will be required prior to review.

9. Project officers or FDA investigators will be invited to attend the RIHSC meeting at which their MON, project, or protocol will be discussed.

Study Summary: A brief summary incorporating the description, purpose and objectives of the study, and how the objectives will be met.

Study Population: Number of kind of subjects needed, including sex and age range.

- A list of specific criteria for subject selection and exclusion, including descriptions of subject solicitation and screening procedures and a listing of criteria to be applied when choosing normals.

A Statement of Risks and Estimation of Probability of Risk Occurrence:

- Statement about the risk to subject in comparison to the sum of the benefit to the subject and/or the importance of the knowledge to be gained.

Alternatives: Alternative procedures that may be equally or more advantageous to the subject, including currently accepted or available therapy.

Other Committee Reviews:

Review and approval by other committees should be indicated. Minutes of meetings at which the proposal was considered, approval memoranda and summaries of substantive disagreement during the review should be attached to the proposal.

- Bureau Scientific Review Committee.

- Ancillary Review Committees (e.g., Review for Radiological Safety).

- Local IRB review - Other reviews

Will the study be done under an IND or IDE?

Monitoring

- Summarize methods by which the subjects will be monitored for adverse or unusual effects during the study.

- If the RIHSC serves as the IRB, list schedule and means by which the RIHSC will be informed about the progress of the study.

II. Guidelines on Informed Consent

- Consent form(s) must be submitted together with protocol.

- All elements of informed consent (21 CFR 50.25) must be present in the consent form.

- A fair explanation of the procedures to be followed, and their purposes, including identification of any procedures which are experimental.

- A description of any reasonably foreseeable attendant discomforts and risks.

- A description of any benefits reasonably to be expected.

- Alternative procedures, if any, that may be advantageous to the subject.

- A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possibility that the FDA may inspect the records.

- For involving more than minimal risk, an explanation as to whether any medical treatment is available if injury occurs and, if so, what it consists of, or where further information may be obtained.

- An explanation of whom to contact to answer any inquiries concerning the research, research subjects rights, or research-related injury to the subject.

- An instruction that the person is free to withdraw his consent and to discontinue participation in the project or activity at any time without prejudice.

- There must be a separate consent form appropriate to each study group.

- A copy of the consent form must be given to the person signing the form.

- The consent form must reflect the changes, if any, recommended by prior reviews (e.g., bureau science committees).

- The procedure for obtaining consent must be discussed. The following questions should be addressed:

- How and when will consent, as referred to in the regulations be obtained?

- How will the study be discussed with the subject?

- Who will be responsible for answering specific questions?

- How much time will be allowed for the subject to read and consider the consent form and to discuss the study prior to signing the form?

- When a "short form" written consent is used, the form must state that the elements of informed consent have been presented orally. A written summary of what is to be said should be submitted to the RIHSC. Refer to 21 CFR 50.27(b)(2) for further guidance.